PONE-D-24-23306Increased resting heart rate indicates strenuous hearts with augmented aortic hydraulic power in hypertensive pigsPLOS ONE

Dear Dr. Lin,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

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Masaki Mogi

Academic Editor

PLOS ONE

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Additional Editor Comments:

Major revisions are necessary in the present form. See the Reviwers’ comments.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Although the topic is interesting, the study is hard to follow in its current form. I have the following comments for the authors to consider.

The title suggests (incorrectly) that increased heart rate is a cause of augmented aortic hydraulic power. Please rewrite accordingly.

The introduction is broad and hard to follow. Overall, the authors should better highlight the current gaps in the literature and the rationale for the present study.

Notably, the first aim of the study was to "clarify whether hypertension develops in AA coarctation porcine model". However, the authors stated in lines 113-115 that they already showed the effectiveness of their model in inducing hypertension (PMID: 29615895). In fact, Figure 1 of both papers is very similar (if not identical). Did you use the same animals? Please clarify.

Lines 116-120: What does Alzheimer's disease have to do with this study?

The time frames for the cluster analysis are not clear. Was it at 8 or 12 weeks? The authors stated that coarctation induced hypertension in all animals at week 12. However, in the cluster analysis, only animals in cluster 1 displayed increases in blood pressure. This is confusing.

Lines 288-290: Didn’t you measure aortic resistance at weeks 8 and 12?

Figures: Please provide the sample size and the number of males/females per group in the figure legends.

It is recommended to show the data as mean � SD in all figures.

It is recommended to include a limitation and perspective/significance section in the discussion.

Reviewer #2: Lin and colleagues determined the pathophysiological changes of the heart in response to hypertension induced by infrarenal abdominal aorta coarctation in miniature pigs. The authors found that 12 weeks of moderate aortic coarctation increased systolic arterial pressure, mean arterial pressure, and heart rate. By clustering the animals into two groups based on the hydraulic power value in the aorta at sacrifice, the author reported that the group with increased aortic hydraulic power demonstrated hypertension and high heart rate compared to the other group and sham controls. Overall, this manuscript could be novel in understanding AA coarctation-induced hypertension as a potential model for studying the pathophysiology of hypertensive heart disease.

Points of concern are outlined below:

Major:

1. The application of coarctation of the infrarenal abdominal aorta (AA) to induce hypertension and subsequent left ventricle (LV) hypertrophy in the current manuscript is questionable. The increase in arterial pressure and heart rate was only observed 12 weeks post-surgery (Fig 1 and Fig 2C), while all parameters assessing LV hypertrophy and myocardial fibrosis were not seen (Fig 5). In addition, the mean pressure in the aorta shows no difference pre- and post-surgery and at sacrifice (Fig 2A). These observations suggest the AA coarctation was either not sufficient or was not applied long enough to induce LV hypertrophy.

2. Why are the diastolic BP and MBP in 8wk and 12wk groups before surgery (Fig 1 E&F) lower than other groups as measured by brachial cuff methods?

3. The criteria used to separate clusters 1 and 2 are inappropriate. While cluster 2 consists of animals from all three treatment groups, 4 of 5 animals in cluster 1 are from the 12w group. Considering that the onset of hypertension was observed around 12 weeks post-surgery (Fig 1), the author should only classify and compare the cluster of animals from the same treatment group.

4. The mean pressure, hydraulic power, and hydraulic energy before surgery and at sacrifice were not different among all groups (Fig 2 A, E&F). Given the critique on the cluster classification above, the application of aortic hydraulic power and MAP&HR to predict HHD progression should be verified in a separate group of animals.

5. Why is the n in Figure 4 less than the one from Figure 3? Were carotid arterial pressure and heart rate only measured in selected animals in Figure 4? Or were the data of some animals excluded? Please provide justification if some data were excluded.

6. Is the n of cluster 1 in Figure 5C equal to 2? If so, the authors should increase the number of samples in cluster 1 for LV hypertrophy assessment.

Minor:

1. Please add n of all groups in all figures.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-24-23306R1Increased resting heart rate indicates high-workload hearts with augmented aortic hydraulic power in hypertensive pigsPLOS ONE

Dear Dr. Lin,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

There are still minor revisions in the present form. 

==============================

Please submit your revised manuscript by Jan 11 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Masaki Mogi

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have adequately addressed my comments, and the manuscript has indeed improved. I have no further concerns.

Reviewer #2: Lin and colleagues determined the pathophysiological changes of the heart in response to hypertension induced by infrarenal abdominal aorta coarctation in miniature pigs. The authors found that 12 weeks of moderate aortic coarctation increased systolic arterial pressure, mean arterial pressure, and heart rate. By clustering the animals into two groups based on the hydraulic power value in the aorta at sacrifice, the author reported that the group with increased aortic hydraulic power demonstrated hypertension and high heart rate compared to the other group and sham controls. Overall, this manuscript could be novel in understanding AA coarctation-induced hypertension as a potential model for studying the pathophysiology of hypertensive heart disease.

Comment to Response #3 to Reviewer 2: Please add this explanation of how cluster analysis is performed to line 289 of the revised manuscript. This information would solve the confusion of how these two clusters are classified.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Increased resting heart rate indicates high-workload hearts with augmented aortic hydraulic power in hypertensive pigs

PONE-D-24-23306R2

Dear Dr. Lin,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Masaki Mogi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Lin and colleagues determined the pathophysiological changes of the heart in response to hypertension induced by infrarenal abdominal aorta coarctation in miniature pigs. The authors found that 12 weeks of moderate aortic coarctation increased systolic arterial pressure, mean arterial pressure, and heart rate. By clustering the animals into two groups based on the hydraulic power value in the aorta at sacrifice, the author reported that the group with increased aortic hydraulic power demonstrated hypertension and high heart rate compared to the other group and sham controls. Overall, this manuscript could be novel in understanding AA coarctation-induced hypertension as a potential model for studying the pathophysiology of hypertensive heart disease. The authors have addressed all my concerns. I have no further comments.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

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